Devices for aerosolization (“dry nebulization”) of aerosolizable dry material are known in which a reservoir is provided comprising aerosolizable material. The aerosolizable material is fed from the reservoir to an aerosolization channel where the aerosolizable material is mixed with carrier gas which is transmitted through the aerosolization channel in pressure pulses. The aerosolizable material is converted to a state in the aerosolization channel which is referred to as aerosol. The particles of the material are, in this case, present in a preferably uniform and finely dispersed form across the entire volume of the carrier gas and are then discharged from the aerosolization channel.
Such devices can be used for administration of medical substances to spontaneously breathing patients and to mechanically ventilated patients. For use in spontaneously breathing patients, the devices are generally connected to a suitable patient interface (e.g., a mouthpiece or a breathing mask). In invasive use or on mechanically ventilated patients, these devices feed the aerosolizable medical substance into a ventilator system which then delivers the aerosolized material to the patient. Possible configurations of such a device for providing the aerosol are described in WO 2006/108558 A1 and WO 2010/122103 A1.
The aerosolizable material contains a therapeutically active substance. In many clinical situations it is desirable to introduce this active substance into the airways of a patient. In order to make sure that an as large as possible fraction of the inhaled particles is deposited in the desired section of the airways (usually the alveoles in the deep lung), it is important that the particles have the right size. By way of example, it has been found that particles which should reach the deep lung should have a mass median aerodynamic diameter (MMAD) in the range of 0.05-10 μm, preferably between 1-5 μm or approximately 3 μm.
Depending on the particular formulation of the therapeutically active substance to be aerosolized, different technical solutions have been proposed. Liquid formulations such as solutions or suspensions can be aerosolized using nebulizers such as a jet nebulizer, hydrosonic wave nebulizer, or pressurized metered dose inhaler (MDI). Dry powder formulations can be aerosolized by use of a dry powder inhaler, DPI. One possible field of application is the application of a pulmonary surfactant or lung surfactant to a patient.
In vertebrates, the inner lung surfaces involved in gas exchange are covered by a thin film of a substance mixture called “pulmonary surfactant” or “lung surfactant”. The most important components of lung surfactant are phospholipids and the so-called surfactant proteins, SP-A, SP-B, SP-C and SP-D. Lung surfactant has surface active properties and reduces surface tension in the alveoli and small airways to such an extent that collapse of the alveoli during exhalation is avoided. The surface tension is regulated dynamically so that the collapse of the alveoli and small airways in favor of the greater ones, which is to be expected according to Laplace's law, is prevented by appropriate adaptation of the surface tension. On the other hand, reduction of surface tension in the alveolar region increases pulmonary compliance, meaning that it facilitates the expansion of the lung upon breathing. The presence of lung surfactant results in a well-balanced and physiologically stable structure of the lung and is vital for the normal function of this organ. While at the time of birth the lungs of mammals contain a sufficient amount of endogenous lung surfactant in order to ensure unrestrained functionality of the lungs from the first breath on, the lungs of prematurely born babies (born below 32 weeks of gestation and especially born below 29 weeks of gestation) are not or not sufficiently capable of producing lung surfactant. This leads to a life-threatening deficiency of oxygen uptake (Infant Respiratory Distress Syndrome, IRDS). IRDS is the main cause of death in prematurely born babies.
Lung surfactant preparations useful to treat Respiratory Distress Syndrome (RDS) such as IRDS can be obtained from the lungs of animals or can be manufactured using the individual components as starting material. For example, WO 92/06703 describes the production of synthetic lung surfactant preparations by evaporating chloroform from a solution comprising phospholipids (such as dipalmitoyl-phosphatidylcholine (DPPC) and dioleylphosphatidyl-ethanolamine (DOPE)) and cholesterol using a rotary evaporator to obtain a thin film which is resuspended in a buffer, if desired together with suitable proteins. EP 0 877 602 discloses the preparation of a synthetic lung surfactant by spray drying a solution of DPPC, palmitoyloleoylphosphatidylglycerol (POPG), palmitic acid, calcium chloride and surfactant protein SP-C.
In certain systems known from the art the aerosolizable material is fed to an aerosolization channel by pressure pulses applied to the aerosolization channel. Examples for such devices are described in WO 2006/108558 A1 and WO 2010/122103 A1. In such a device there is normally an open connection between the reservoir comprising the aerosolizable material and the aerosolization channel. The pressure differences occurring when a patient is inhaling or exhaling or which occur at ventilated patients are also transferred to the reservoir comprising the aerosolizable material. Pressure changes also may occur in case of ventilated patients when the tubing used to provide the patient with breathing air is partly or totally blocked, or if one of the tubes of the ventilation system snaps off. When a blockage occurs, the pressure in the reservoir may also rise. As the amount of aerosolizable material provided to the aerosolization channel mainly depends on the pressure difference between the reservoir and the aerosolization channel, an increased pressure in the reservoir may lead to a larger amount of aerosolizable material provided to the aerosolization channel, which then can be too large to be uniformly dispersed in the compressed gas.